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| Subject Categories: Chromatin & Transcription | Molecular Biology of Disease |
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| The EMBO Journal
(2006) 25, 1253–1262, doi:10.1038/sj.emboj.7601021 Published online 23 February 2006 |
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In vivo role of the HNF4 AF-1 activation domain revealed by exon swapping |
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| Nadège Briançon and Mary C Weiss |
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Unité de Génétique de la Différenciation, URA 2578 du CNRS, Département de Biologie du Développement, Institut Pasteur, Paris, France To whom correspondence should be addressed Mary C Weiss, Unité de Génétique de la Différenciation, URA 2578 du CNRS, Département de Biologie du Développement, Institut Pasteur, 75724 Paris Cedex 15, France. Tel.: +33 1 4568 8500; Fax: +33 1 4061 3231; E-mail: mweiss@pasteur.fr Received 5 October 2005; Accepted 2 February 2006; Published online 23 February 2006. |
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| Abstract |
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| The gene encoding the nuclear receptor hepatocyte nuclear factor 4 (HNF4) generates isoforms HNF41 and HNF47 from usage of alternative promoters. In particular, HNF47 is expressed in the pancreas whereas HNF41 is found in liver, and mutations affecting HNF4 function cause impaired insulin secretion and/or hepatic defects in humans and in tissue-specific 'knockout' mice. HNF41 and 7 isoforms differ exclusively by amino acids encoded by the first exon which, in HNF41 but not in HNF47, includes the activating function (AF)-1 transactivation domain. To investigate the roles of HNF41 and HNF47 in vivo, we generated mice expressing only one isoform under control of both promoters, via reciprocal swapping of the isoform-specific first exons. Unlike Hnf4 gene disruption which causes embryonic lethality, these '7-only' and '1-only' mice are viable, indicating functional redundancy of the isoforms. However, the former show dyslipidemia and preliminary results indicate impaired glucose tolerance for the latter, revealing functional specificities of the isoforms. These 'knock-in' mice provide the first test in vivo of the HNF4 AF-1 function and have permitted identification of AF-1-dependent target genes. |
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| Keywords: activation function, isoform, lipid metabolism, nuclear receptor 2a1, type II diabetes mellitus |
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Top of page MORE ARTICLES LIKE THISThese links to content published by NPG are automatically generated RESEARCHThe orphan nuclear receptor HNF4α determines PXR- and CAR-mediated xenobiotic induction of CYP3A4 Nature Medicine Article (01 Feb 2003) |
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